Neuroprotective Mitochondrial Glutamate Receptors

Science Signaling  23 Oct 2012:
Vol. 5, Issue 247, pp. ec272
DOI: 10.1126/scisignal.2003712

Glutamate receptors of the N-methyl-D-aspartate (NMDA) type participate in both physiological and pathological synaptic events, with excessive activation of these receptors resulting in calcium overload and excitotoxicity. Korde and Maragos prepared isolated mitochondria from rat brains and found that these preparations responded to glutamate or NMDA agonists with increased calcium uptake, compared with the calcium uptake by mitochondria in the absence of these ligands. The NR2a subunit of the NMDA receptor was detected to be associated with mitochondria by electron microscopy of purified mitochondrial preparations or hippocampal slices, and Western blotting of submitochondrial preparations indicated that the NR1 and NR2a subunits were associated with the inner mitochondrial membrane. Mitochondria prepared from GT1-7, a neuronal cell line, in which the NR1 subunit was knocked down exhibited only basal calcium uptake that was not enhanced by the addition of NMDA. In contrast, expression of NR1 and NR2a targeted specifically to the mitochondria resulted in cells that had enhanced ATP production and exhibited less death in response to cytotoxic concentrations of glutamate. Mitochondria from these NMDA receptor–targeted cells had increased calcium uptake, suggesting that increased capacity for calcium buffering may contribute to the protective effects. Although compared with their abundance in the synaptic plasma membrane, the abundance of NMDA receptors in mitochondria is low, these data suggest that mitochondrial NMDA receptors may play a role in the calcium buffering capacity of mitochondria.

A. S. Korde, W. F. Maragos, Identification of an N-methyl-D-aspartate receptor in isolated nervous system mitochondria. J. Biol. Chem. 287, 35192–35200 (2012). [Abstract] [Full Text]